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Nonlinear ordinary differential equations (ODEs) are common in pharmacokinetic–pharmacodynamic systems. Although their exact solutions cannot generally be determined via algebraic methods, their rapid and accurate solutions are desirable. Thus, numerical methods have a critical role. Inductive Linearization was proposed as a method to solve systems of nonlinear ODEs. It is an iterative approach that converts a nonlinear ODE into a linear time-varying (LTV) ODE, for which a range of standard integration techniques can then be used to solve (e.g., eigenvalue decomposition [EVD]). This study explores the properties of Inductive Linearization when coupled with EVD for integration of the LTV ODE and illustrates how the efficiency of the method can be improved. Improvements were based on three approaches, (1) incorporation of a convergence criterion for the iterative linearization process (for simulation and estimation), (2) creating more efficient step sizes for EVD (for simulation and estimation), and (3) updating the initial conditions of the Inductive Linearization (for estimation). The performance of these improvements were evaluated using single subject stochastic simulation-estimation with an application to a simple pharmacokinetic model with Michaelis–Menten elimination. The reference comparison was a standard non-stiff Runge–Kutta method with variable step size (ode45, MATLAB). Each of the approaches improved the speed of the Inductive Linearization technique without diminishing accuracy which, in this simple case, was faster than ode45 with comparable accuracy in the parameter estimates. The methods described here can easily be implemented in standard software programme such as R or MATLAB. Further work is needed to explore this technique for estimation in a population approach setting.

We detected Helicobacter cinaedi in 4 of 10 patients with infected aortic aneurysms diagnosed using blood or tissue culture in Aichi, Japan, during September 2017-January 2021. Infected aortic aneurysms caused by H. cinaedi had a higher detection rate and better results after treatment than previously reported, without recurrent infection.

A 34-year-old man with no medical history presented with fever 4 days after receiving the first dose of mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. He had no prior clinical evidence of severe acute respiratory syndrome coronavirus 2 infection and was negative for serial polymerase chain reaction testing. Ten days after vaccination, he was referred to our hospital because of no response to antibiotics and the emergence of neutropenia, thrombocytopenia, and liver dysfunction. Blood tests also showed elevated serum ferritin and plasma soluble interleukin-2 receptors. Serological and PCR testing excluded active infections of cytomegalovirus, Epstein-Barr virus, and hepatitis viruses. Blood culture yielded no growth. Computed tomography revealed mild hepatosplenomegaly and porta hepatis lymphadenopathy but no focus on infection. Bone marrow aspiration demonstrated hemophagocytosis but no infiltrating lymphoma cells. Immediately, 2-mg/kg intravenous methylprednisolone was commenced based on the presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH), leading to the rapid and durable improvement of his symptoms and laboratory data. Later, without other causes triggering hemophagocytosis, and with the close link between vaccination and disease onset, the final diagnosis of vaccination-induced secondary HLH was made. HLH after COVID-19 vaccination, though extremely rare, can occur regardless of the vaccine type. Therefore, clinicians should recognize and deal with this occasionally fatal adverse event.

Posaconazole is a globally approved broad-spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. This article aims to describe a model-informed approach for dose justification of posaconazole in the Japanese population as either high-risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients). A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients. The PK profiles and exposure distributions in Japanese patients were predicted and compared against foreign patients, that is, patients outside of Japan. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients.

Coronavirus disease 2019 (COVID-19) is associated with various symptoms and changes in hematological and biochemical variables. However, clinical features, which can differentiate COVID-19 from non-COVID-19, are not clear. We therefore examined the key clinical features of COVID-19 and non-COVID-19 patients. This study included 60 COVID-19 patients and 100 non-COVID-19 patients, diagnosed by PCR, and no significant differences in the age and sex were seen between the two groups. The frequencies of fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, taste dysfunction, underlying hyperlipidemia, and the prescription of angiotensin II receptor blocker (ARB) were significantly higher in COVID-19 patients than those in non-COVID-19 patients. The counts of leucocytes, neutrophils, lymphocytes, eosinophils, monocytes, and basophils and the levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The frequencies of atypical lymphocytes and the levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19 than those in non-COVID-19. The C-reactive protein (CRP) level in COVID-19 patients was significantly lower than that in non-COVID-19 patients, when we compared CRP levels among patients with elevated CRP. This study is the first to indicate that electrolyte levels and the frequency of atypical lymphocytes in COVID-19 are significantly different from those in non-COVID-19. Fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, and taste dysfunction were the key symptoms of COVID-19. Furthermore, hyperlipidemia and ARB may be risk factors of COVID-19. In conclusion, leucocytes, leucocyte fractions, CRP, LDH, and electrolytes are useful indicators for COVID-19 diagnosis.

A 26-year-old woman complained of upper abdominal pain. Computed tomography (CT) showed acute pancreatitis, a left adrenal tumor and solitary right pulmonary metastasis. She underwent left adrenalectomy; the adrenal tumor was diagnosed as adrenocortical carcinoma (ACC). When preparing to resect the pulmonary metastasis, she suffered a second acute pancreatic attack. Magnetic resonance cholangiopancreatography (MRCP) showed that the proximal main pancreatic duct (MPD) was dilated, and the distal MPD was diminished; however, no pancreatic tumor was observed on CT or MRCP. Endoscopic ultrasonography revealed a solitary pancreatic mass, which was diagnosed as pancreatic metastasis from ACC by endoscopic ultrasonography-guided fine-needle aspiration.

Introduction The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. Methods J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. Results Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers’ diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. Conclusions We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models.

Japanese scallops Patinopecten yessoensis are one of the main marine products of Hokkaido, Japan. In addition to adductor muscle, scallop mantle tissue is also eaten in Japan. We fed Wistar rats diets containing the scallop mantle epithelial cell layer for 3–8 weeks and compared the outcomes with a control group. No differences in general appearance or behavior were observed between the groups for the first 2 weeks. Thereafter, a significant decrease in food consumption was observed, and the treated rats died between 6 and 8 weeks. Serum biochemistry and histological studies revealed nephrotoxicity and hepatotoxicity in rats fed scallop mantle epithelial cells. Glucose tolerance tests showed that feeding scallop mantle epithelial cells to rats causes a glucose metabolism disorder. A diet containing a water extract from scallop mantle epithelial cells caused toxicity in mice, but a diet containing a methanol extract, which dissolves diarrhetic shellfish poisoning (DSP) toxin, or an extract in heated 0.1 M HCl, which dissolves paralytic shellfish poisoning (PSP) toxin, did not cause toxicity. Mice fed a diet containing pronase-treated water extract neither showed a decrease in their food intake nor death. These results suggest that a water-soluble component other than DSP or PSP toxin causes toxicity.

A 58-year-old Japanese man with a high parasitemia of Plasmodium falciparum, returning from Uganda, was admitted to our hospital since his consciousness level rapidly deteriorated after the initial dose of mefloquine. Despite the parasitemia was cleared by quinine by day 7, the coma remained unchanged and diffuse leukoencephalopathy was detected on magnetic resonance image. Steroid pulse therapy was initiated on day 8. Subsequently, the neurological manifestations improved and he was discharged on day 73 without any sequelae. Pathogenesis of P. falciparum causing cerebral malaria is diverse and complex. If neurological symptoms unusually prolong, steroid may be an effective treatment option.

Relationships between the plasma concentration of a cathepsin K inhibitor (ONO-5334) and inhibition of bone resorption markers N-telopeptide of type I collagen (NTX) and C-telopeptide of type I collagen (CTX) in serum and urinary NTX/creatinine and CTX/creatinine were examined in 10 postmenopausal women. The subjects received slow-release tablets of 100 mg ONO-5534 under fasted or fed conditions in a study with a crossover design. Inhibition of serum NTX and CTX levels and plasma concentrations of ONO-5334 were monitored at 0, 24, 48 and 168 h after dosing. Changes in urinary NTX/creatinine and CTX/creatinine levels in second morning urine were evaluated on 0, 1, 2 and 7 days after dosing. Data were analyzed using sigmoid maximal drug effect (Emax) models. The maximal inhibition, estimated Emax values, were − 31.8% for serum NTX, − 53.1% for serum CTX, − 67.2% for urinary NTX/creatinine, and − 95.2% for urinary CTX/creatinine. The estimated half maximal effective plasma concentrations (EC50) of ONO-5334 and confidence intervals were 1.79 (1.01 to 3.16) ng/mL for serum NTX, 2.07 (1.63 to 2.62) ng/mL for serum CTX, 1.85 (1.30 to 2.61) ng/mL for urinary NTX/creatinine, and 1.98 (0.94 to 3.76) ng/mL for urinary CTX/creatinine. EC50 values for the four crosslinks did not significantly differ, as indicated by the overlapping 95% confidence intervals. The highest signal-to-noise ratio was achieved with serum CTX, and was 2-fold higher than that on serum NTX. Inhibition for serum NTX and CTX, and urinary NTX/creatinine and CTX/creatinine by ONO-5334 were all correlated with correlation coefficients ranging from 0.55 to 0.80. In conclusion, data of ONO-5334 slow-releasing tablets in postmenopausal women were well fitted in Emax model. In all measured telopeptides, the maximal inhibition was obtained at urinary CTX/creatinine level, but serum CTX had the highest signal-to-noise ratio. Inhibition for all measured telopeptides by ONO-5334 were all correlated. The estimated half maximal effective plasma concentrations were not significantly different between all measured telopeptides.

Integrating quantitative systems pharmacology (QSP) into pharmacokinetics/pharmacodynamics (PKPD) has resulted in models that are highly complex and often not amenable to further exploration via estimation or design. Because QSP models are usually depicted using nonlinear differential equations it is not straightforward to apply some model reduction techniques, such as proper lumping. In this study, we explore the combined use of linearization and proper lumping as a general method to simplification of a nonlinear QSP model. We illustrate this with a bone biology model and the reduced model was then applied to describe bone mineral density (BMD) changes due to denosumab dosing. The methodologies used in this study can be applied to other multiscale models for developing a mechanism-based structural model for future analyses.

In recent years, malware aims at Android OS has been increasing due to its rapid popularization. Several studies have been conducted for automated malware detection with machine learning approach and reported promising performance. However, they require a large amount of computation when running on the client; typically mobile phone and/or similar devices. Thus, problems remain in terms of practicality. In this paper, we propose an accurate and light-weight Android malware detection method. Our method treats very limited part of raw APK (Android application package) file of the target as a short string and analyzes it with one-dimensional convolutional neural network (1-D CNN). We used two different datasets each consisting of 5,000 malwares and 2,000 goodwares. We confirmed our method using only the last 512–1K bytes of APK file achieved 95.40–97.04% in accuracy discriminating their malignancy under the 10-fold cross-validation strategy.

Lignosulfonic acid is a waste lignin produced from the sulfite pulping of softwood. We investigated the effect of lignosulfonic acid on α-glucosidase and found that lignosulfonic acid produced a reversible and non-competitive inhibition of the enzyme activity. Moreover, in human colorectal adenocarcinoma cells, lignosulfonic acid inhibited 2-deoxyglucose uptake, while in vivo studies demonstrated a significant reduction in the blood glycemic response to sucrose or glucose ingestion in rats treated with lignosulfonic acid. Feces of rats fed a diet supplemented with 5% lignosulfonic acid had higher sugar content compared to those of rats fed a control diet. These results suggest that lignosulfonic acid suppresses the rise in blood glucose levels through inhibition of α-glucosidase activity and intestinal glucose absorption.

Quantitative systems pharmacology (QSP) models are increasingly used in drug development to provide a deep understanding of the mechanism of action of drugs and to identify appropriate disease targets. Such models are, however, not suitable for estimation purposes due to their high dimensionality. Based on any desired and specific input-output relationship, the system may be reduced to a model with fewer states and parameters. However, any simplification process will be a trade-off between model performance and complexity. In this study, we develop a weighted composite criterion which brings together the opposing indices of performance and dimensionality. The weighting factor can be determined by qualification of the simplified model based on a visual predictive check (VPC) using the precision of each parameter. The weighted criterion and model qualification techniques were illustrated with three examples: a simple compartmental pharmacokinetic model, a physiologically based pharmacokinetic (PBPK) example, and a semimechanistic model for bone mineral density. When considering the PBPK example, this automated search identified the same reduced model which had been detected in a previous report, as well as a simpler model which had not been previously identified. The simpler bone mineral density model provided an adequate description of the response even after 1 year from the initiation of treatment. The proposed criterion together with a VPC provides a natural way for model order reduction that can be fully automated and applied to multiscale models.

Background The Research Group on Chemotherapy of Tropical Diseases, Japan, introduced artemether–lumefantrine (AL) in late 2002, mainly for treating uncomplicated Plasmodium falciparum malaria. Because AL was on the market in Japan in March 2017, the effectiveness and safety of AL were analyzed to help medical personnel use AL optimally. Methods Case report forms submitted by the attending physicians were analyzed. When necessary, direct contact with the attending physicians was made to obtain detailed information. Results Effectiveness analysis was performed for 62 cases and safety analysis was performed for 66 cases. In P. falciparum malaria, the overall cure rate was 91.1% (51/56), of which the cure rates for Japanese and non-Japanese patients were 82.1% (23/28) and 100% (28/28), respectively. The successfully treated cases included severe P. falciparum malaria, with parasite densities exceeding 500,000/μL. Adverse events were reported in 14 patients, including delayed hemolytic anemia which occurred in the top four highest parasitemic cases. Conclusions AL treatment failure in P. falciparum malaria may not be rare among non-immune individuals, including Japanese. The possibility of delayed hemolytic anemia, which occurs preferentially in high parasitemic cases, should be considered following AL treatment.

Delayed haemolytic anaemia has been reported in association with intravenous artesunate treatment in patients with severe Plasmodium falciparum malaria, and furthermore, oral artemisinin-based combination therapies including artemether-lumefantrine (AL) have also been incriminated. However, definite cases of delayed haemolytic anaemia associated with AL appear to be scarce, as reported cases were often treated concomitantly with other anti-malarials. In this study, we report a severe case of delayed haemolytic anaemia following AL alone in a Japanese traveller with severe parasitaemia caused by numerous P. falciparum parasites and a few P. vivax parasites. We also stress the need by further studies to differentiate between delayed haemolytic anaemia and blackwater fever, the latter being another malaria-related haemolytic condition, more clearly than they are now.

Introduction With ever-growing global exchanges, the number of travelers, including pregnant women, to the tropics is increasing, which poses a risk of contracting malaria. Although there are several reports on imported malaria in pregnancy from Western countries, those focusing on cases experienced in Japan are very limited. Methods We searched for cases of malaria in pregnancy in the treatment records submitted to the Research Group on Chemotherapy of Tropical Diseases, Japan, during the period 1993–2016. Literature searches were also conducted using an American and a Japanese search system. Results Ten cases of malaria in pregnant women were identified, including four cases with Plasmodium falciparum. Of eight evaluable cases, only one practiced malaria chemoprophylaxis. Among the nine evaluable cases, eight resulted in uneventful delivery and one P. falciparum case developed severe hepatic disturbance, disseminated intravascular coagulation, and intrauterine fetal death. After the initial attack, none of the Plasmodium vivax/Plasmodium ovale cases practiced chloroquine prophylaxis until delivery. One P. ovale case received a lower dose regimen of chloroquine as acute-stage therapy. Conclusion This study demonstrated additional cases of imported malaria in pregnant women to the literature and highlighted various epidemiological, demographic, and clinical characteristics. Some of the clinical issues raised need to be investigated. Due to the paucity of the cases worldwide, sharing information among various countries is indispensable, and international guidelines which are now increasingly recommending the use of artemisinins in pregnant women should be referred.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).

Pharmacokinetic-pharmacodynamic systems are often expressed with nonlinear ordinary differential equations (ODEs). While there are numerous methods to solve such ODEs these methods generally rely on time-stepping solutions (e.g. Runge-Kutta) which need to be matched to the characteristics of the problem at hand. The primary aim of this study was to explore the performance of an inductive approximation which iteratively converts nonlinear ODEs to linear time-varying systems which can then be solved algebraically or numerically. The inductive approximation is applied to three examples, a simple nonlinear pharmacokinetic model with Michaelis-Menten elimination (E1), an integrated glucose-insulin model and an HIV viral load model with recursive feedback systems (E2 and E3, respectively). The secondary aim of this study was to explore the potential advantages of analytically solving linearized ODEs with two examples, again E3 with stiff differential equations and a turnover model of luteinizing hormone with a surge function (E4). The inductive linearization coupled with a matrix exponential solution provided accurate predictions for all examples with comparable solution time to the matched time-stepping solutions for nonlinear ODEs. The time-stepping solutions however did not perform well for E4, particularly when the surge was approximated by a square wave. In circumstances when either a linear ODE is particularly desirable or the uncertainty in matching the integrator to the ODE system is of potential risk, then the inductive approximation method coupled with an analytical integration method would be an appropriate alternative.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

A 58-year-old Japanese man with a high parasitemia of Plasmodium falciparum, returning from Uganda, was admitted to our hospital since his consciousness level rapidly deteriorated after the initial dose of mefloquine. Despite the parasitemia was cleared by quinine by day 7, the coma remained unchanged and diffuse leukoencephalopathy was detected on magnetic resonance image. Steroid pulse therapy was initiated on day 8. Subsequently, the neurological manifestations improved and he was discharged on day 73 without any sequelae. Pathogenesis of P. falciparum causing cerebral malaria is diverse and complex. If neurological symptoms unusually prolong, steroid may be an effective treatment option.

The efficient one-pot umpolung α-phenylation of ketones via N -alkenylisoxazolidine is described. When the various ketones are treated with triphenylaluminum prepared from phenylmagnesium chloride and AlCl 3 in the presence of isoxazolidine, the desired products are obtained in good to moderate yield. This method is equivalent to a direct α-arylation reaction of carbonyl groups.

We report results of our investigation of the case of a 34-year-old woman (YJ) who showed persistent left unilateral spatial neglect (USN) in daily living, frequently hitting obstacles or bumping into the wall, although her visuospatial ability was mostly preserved in paper and pencil neuropsychological tests. In order to clarify this apparent discrepancy, her eye fixation pattern was monitored in testing situations and in natural daily activities using an eye camera. The results showed that when taking the standard tests YJ tended to shift her fixation point to the left edge of the testing frame to overcome over-searching tendency to the right as left hemianopics without left USN would do. However in natural situations, this compensatory leftward fixation was not found. This may be due to the lack of adequate frames of reference in the natural environment. Our findings suggest limitation of laboratory neuropsychologicial testing to fully appreciate the scope of a patient's disability in natural settings.

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an Imax value of 0.828 and an IC50 value of 1.29 ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd.

記憶検査課題において，AD の虚再生 (非学習材料の産出) はよくみられる現象である。本研究では WMS-R 言語性対連合課題を用い，AD (59 名) の虚再生反応を調べ，記憶，注意，そして意味流暢性との関連を検討した。結果，(1) 虚再生は課題の学習難易度に影響を受けず，記憶障害と虚再生は相関しなかった。(2) 虚再生・無再生の出現量によって対象を3 群に分類し，各群の認知機能の特徴を比較したところ，学習難易度の高い対連合学習課題で虚再生が増えるほど，意味流暢性課題と数唱の成績が低下する傾向があった。以上より AD の虚再生は，意味記憶の非効率利用や注意および遂行機能低下との関連が深いと考えられた。

Ruthenium thin films were deposited using a new novel Ru precursor, bis(acetylacetonato)(η4-1,5-hexadiene)ruthenium, Ru(acac)2(hd). Ru(acac)2(hd) is a brown viscous liquid and stable in moisture and air at room temperature. The resisitivity, microstructure and surface morphology of the deposited Ru thin films were examined. The Ru thin films had a low resistivity of 12.5 µΩcm at 360 °C. A very small amount of O2 gas (0.5% O2 gas concentration) is necessary as a reactant gas to decrease the resistivity of the Ru thin films. X-ray photoelectron spectroscopy (XPS) showed that the Ru thin films contained no carbon and oxygen impurities. The Ru thin film surface was fairly smooth, as measured by atomic force microscopy (AFM). The root-mean-square (RMS) roughness of the Ru thin films was 0.91 nm.

Self-controlled synchronous motors have been used as variable speed motors in industry and are now also used for propelling ships. In this type of motor, information on the rotor position is needed in order to achieve stable operation. A simple sensorless starting method for this motor is studied in this paper. An initial rotor position detection method without a position sensor is first discussed. It is shown that the position can be detected easily by observing the electromotive forces induced in the armature windings due to the change in the field current. Then, a new starting method for the motor is proposed on the basis of DC link current chopping during the starting period. It is shown that, based on the proposed method, starting of the motor can be realized independently of the load conditions, which indicates the usefulness of the proposed method. Finally, the effects of various system parameters on the response of the DC input current and the motor speed during starting up are discussed. © 2011 Wiley Periodicals, Inc. Electr Eng Jpn, 175(3): 48–55, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/eej.21082

As the SC system spread, activities of clinical psychologists in school became outreach style and SC-Teacher collaboration is becoming an important issue. In this paper, we reconsider the "collaboration", which clarify the "roles" of teachers and SCs, and propose a new paradigm. In previous research (Takashima et al., 2007, 2008), both Japanese SCs and teachers had "SC-like" and "teacher-like" viewpoints, and inspite of their job type their individual "way of reviewing cases" ("perspective") existed as an internal framework. In this study, comparing the practice of Western (Swiss) SPs who function independently, it was discovered that Japanese SC relations are characterized by an "understanding of feelings." In order to create SC-Teacher collaborations, there is a need for a relational "multiple viewpoint mode" that takes advantage of Japanese mentality. This approach will have them reflect their own mind towards their "viewpoints" and "perspectives," rather than defining people and events through static, substantive "roles."

Pranlukast is a cysteinyl leukotriene receptor antagonist that has been used to treat bronchial asthma and allergic rhinitis. In vitro data suggest that pranlukast is a substrate of CYP3A4. Thus, the effect of clarithromycin, a potent CYP3A4 inhibitor, on the pharmacokinetics of pranlukast was examined in an open-label, randomized, two-way crossover study in 16 healthy male volunteers. In treatment A, volunteers received a single, 225 mg dose of pranlukast. In treatment B, 200 mg of clarithromycin was administered twice daily for 7 days and a single, 225 mg dose of pranlukast was coadministered on day 7. Blood samples were collected up to 24 hours after treatment, and pranlukast concentrations in the plasma were measured. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for pranlukast AUC(0-infinity) and C(max) (with/without clarithromycin) were 1.06 (0.91, 1.24) and 1.17 (0.95, 1.45), respectively. In conclusion, clarithromycin and pranlukast could be coadministered without dose adjustment because clarithromycin minimally affected the pharmacokinetics of pranlukast.